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Feasibility of Randomized Controlled Trials for Cancer Drugs Approved by the Food and Drug Administration Based on

Rebekah Rittberg1, Piotr Czaykowski1,2,3, Saroj Niraula1,2

  • 1Section of Hematology/Oncology, Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.

JNCI Cancer Spectrum
|August 19, 2021
PubMed
Abstract

Insights

Most US Food and Drug Administration (FDA) drug approvals using single-arm studies (SAS) could feasibly be conducted as randomized controlled trials (RCTs) within similar timeframes. This suggests SAS should be reserved for exceptional circumstances to maintain patient safety and scientific integrity.

Area of Science:

  • Oncology
  • Clinical Trials
  • Drug Approval Process

Background:

  • The US Food and Drug Administration (FDA) utilizes an Accelerated Approval (AA) pathway to expedite patient access to novel therapeutics.
  • This pathway often permits less rigorous study designs, such as single-arm studies (SAS), due to perceived difficulties in conducting timely randomized controlled trials (RCTs).

Purpose of the Study:

  • To evaluate the feasibility of conducting randomized controlled trials (RCTs) for solid tumors approved via the FDA's Accelerated Approval (AA) pathway using single-arm studies (SAS).
  • To compare the sample sizes and accrual durations required for hypothetical RCTs against the characteristics of existing SAS-based approvals.

Main Methods:

  • Hypothetical RCTs were designed with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) as endpoints.
  • Existing standards of care were used as controls, with 1:1 randomization, 80% power, and a 5% alpha error rate.
  • Accrual durations were estimated based on US cancer incidence and mortality rates, assuming less than 5% patient participation.

Main Results:

  • Of 172 drug approvals for solid tumors between 2010-2019, 31 (18.0%) were based on SAS, with 77.4% utilizing the AA pathway.
  • Median sample size for SAS was 104. Median sample sizes needed for RCTs were 206 (ORR), 130 (PFS), and 396 (OS).
  • RCTs were theoretically feasible within durations comparable to SAS for 84.6% (ORR), 94.1% (PFS), and 80.0% (OS) of approvals.

Conclusions:

  • A significant majority of FDA drug approvals based on SAS could likely be achieved through RCTs in a comparable timeframe.
  • The reliance on SAS for drug approval may not be necessary in most cases and could potentially compromise scientific rigor and patient safety.
  • Exceptional circumstances should be the primary criterion for permitting drug approval based on SAS.

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